Atherosclerosis isadiseasecharacterizedbylesionslocatedinthewallofbloodvessels.Thelesionsareinducedbydisordersthatinjuretheendothelium,suchashypertension,diabetes,andsmoking.Threeformedelements(monocytes,Tlymphocytes,andplatelets)thatcirculateinthebloodstreamactonthedamagedvascularendothelium.There,theygeneratechemotacticfactorsandmitogensthatmodifythestructureofthesurroundingsmoothmusclecells.ThelatterlosemostoftheirthickandthinfilamentsanddevelopanextensiveroughendoplasmicreticulumandGolgicomplex.Thesecellsmigratetothesubendothelialspace(i.e.,thetunicamediaoftheartery),proliferate,andparticipateinformationofthefattylesionsorthefibrousplaquesthatcharacterizeatherosclerosis.InhibitionordownregulationofRhokinase(ROK)hasbeenshowntopromoteregressionofatherosclerotic-likelesionsinananimalmodel.ThemechanismormechanismsunderlyingthisbeneficialeffectofROKinhibitionareunclearbutmayberelatedtoregulationofbothendothelialpermeabilityandmonocytemigrationbyROK.Thatis,hyperactivityofROKhasbeenimplicatedinvariouspathologicalconditions,includingincreasedtransendothelialpermeability(perhapssecondarytoincreasedactomyosinactivity),whereasinhibitionofROKhasbeenshowntodecreasetransendothelialmigrationofmonocytesandneutrophils.
Biophysical Properties of Smooth Muscle
Smooth muscle contains large amounts of connective tissue composed of extensible elastin fibrils and inextensible collagen fibrils. Because this extracellular matrix can withstand high distending forces or loads, it is responsible for the passive length-tension curve measured in relaxed tissues. This ability of the matrix also limits organ volume.
When lengths are normalized to the optimal length for development of force (i.e., L0), the length-tension curves for smooth and skeletal muscle are very similar (
Fig. 14.15 ). However, the length-tension curves of striated and smooth muscle differ quantitatively. For example, smooth muscle cells shorten more than skeletal muscle cells do. In addition, smooth muscle is characteristically only partially activated, and the peak isometric force attained varies with the stimulus. In skeletal muscle the stimulus (i.e., action potential) always produces a full twitch contraction. Smooth muscle can generate active force comparable to that of skeletal muscle, even though smooth muscle contains only about a fourth as much myosin. This does not imply that the cross-bridges in smooth muscle have greater force-generating capacity. Instead, active cross-bridges in smooth muscle are much more likely to be in 2.4 2.0 1.6 1.2 0.8 0.4 0.6 0.8 1.0 1.2 Po = 2.22 ± 0.17 × 106 dynes/cm2 N = 11 •Fig. 14.15 Lengthdependenceofcontractionofsmoothmuscleshowsabell-shapedresponsesimilartothatseeninskeletalmuscle.Thesmoothmusclestripswereobtainedfromhogcarotidartery.Contractionwasinducedbypotassiumdepolarization.Optimalmusclelength(Lo)wasgraphicallydeterminedasthelengthatwhichmaximaltension(Po)wasdeveloped.Redcircles,passivetension;bluecircles,activetension,triangles,totaltension;(FromHerlihyJT,MurphyRA.Circ. Res. 1973;33:275-283.) the attached force-generating configuration because of their slow cycling kinetics.